ABSTRACT Nonmelanoma skin cancer, which includes squamous cell carcinoma (SCC), is the most common cancer diagnosed in the United State,s with the overwhelming majority of cases resulting from ultraviolet (UV) irradiation. SCC usually develop from premalignant precursors, providing an opportunity for intervention to prevent malignant disease and metastatic progression. Treatment of clinically detectable malignant lesions and precursor actinic keratoses still relies largely on surgical excision. These procedures are invasive, carry a significant healthcare cost, and are often an insufficient means of preventing metastatic progression in immunocompromised patients. Consequently, there is a need for more effective mechanism-based treatments with no or minor side effects. In preliminary investigations, we showed that increased nuclear transporter exportin (XPO)1 drives aberrant localization of the scaffolding and signaling protein 14-3-3? to activate prosurvival pathways in SCC cells. Genetic deletion of the gene for 14-3-3? suppressed tumor development by 75% and blocked malignant progression while nontumorigenic skin cells were unaffected by the lack of 14-3- 3?. Consequently, our hypothesis is that inhibiting two key regulators that drive aberrant prosurvival signaling will provide a novel and effective means to prevent skin tumor growth and malignant progression with minimal toxicity to the surrounding normal skin. In the proposed research we will delineate the mechanisms and consequences of XPO1-driven aberrant 14-3-3? signaling for malignant keratinocytes (Aim 1), improve upon candidate agents we have developed that disrupt 14-3-3? prosurvival signaling (Aim 2), and provide proof-of- principle evidence of the efficacy of 14-3-3? and XPO1 inhibitors for the prevention of skin tumor development and progression using human patient derived (PDX) and UV irradiation-induced skin cancer models. Successful completion of this work is anticipated to lead to novel approaches for the prevention and treatment of skin cancer.